Isoxazole substituted nitroimidazoles

ABSTRACT

Novel substituted nitroimidazoles are provided, for example, 2-(4,5-substituted-isoxazol-3-yl)-1-substituted-5-nitroimidazole; 2-(4,5-disubstituted-Δ 2  -isoxazolin-3-yl)-1-substituted-5-nitroimidazole; or 2-(4,5-disubstituted-2-loweralkyl-isoxazolidin-3-yl)-1-substituted-5-nitroimidazole. These compounds have antibacterial and antiprotozoal activity, especially against human and animal trypanosomiasis and trichomoniasis.

This is a division of application Ser. No. 301,420 filed Oct. 27, 1972.

This invention relates to isoxazol-3-yl-, Δ² -isoxazolin-3-yl-, orisoxazolidin-3-yl-substituted-5-nitroimidazoles.

These compounds have the following respective structures: ##STR1##WHEREIN R₁ is hydrogen, loweralkyl having 1-6 carbon atoms, or --CH₂ CH₂OH, Y is loweralkyl having 1-6 carbon atoms, benzyl, or hydrogen, R₂ andR₃ are the same or different and are each hydrogen, loweralkyl having1-6 carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl,carboxamidodialkyl, amino, phenyl, aminoalkyl, aminodialkyl, or R₂ andR₃ are a ring structure having the following structure: ##STR2## and R₄and R₅ are the same or different and are each hydrogen, loweralkylhaving 1-6 carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl,carboxamidodialkyl, amino, phenyl, aminoalkyl, or aminodialkyl; or R₄and R₅ are a ring structure of

Ch_(2n), n equals an integer from 3-10;

except that when only one of R₂ and R₃ or R₄ and R₅ are hydrogen, thesubstituent other than hydrogen is on the 5-position of the ring.Whenever the term alkyl is used throughout the specification, a loweralkyl group having 1-6 carbon atoms is intended.

The novel compounds disclosed in this invention are prepared followingthree different processes. The isoxazolyl derivatives are prepared byreacting an acetylene derivative with a1-loweralkyl-5-nitroimidazol-2-hydroxamoyl chloride.

The Δ² -isoxazolinyl derivatives are prepared by reacting an olefin witha 1-loweralkyl-5-nitroimidazol-2-hydroxamoyl chloride.

The isoxazolidinyl derivatives are prepared by reacting an olefin withan α-(1-methyl-5-nitroimidazol-2-yl)-N-alkylnitrone. These processes areseparately discussed in greater detail hereinafter.

The reactive olefin used to prepare both the Δ² -isoxazolinyl and theisoxazolidinyl derivatives can be defined as ##STR3## wherein R₂ and R₃are the same or different and are each hydrogen, loweralkyl having 1-6carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl,carboxamidodialkyl, phenyl, or R₂ and R₃ are a ring structure having thefollowing structure: ##STR4##

The acetylene compound used to prepare the isoxazolyl derivative can bedefined as

    R.sub.4 --C.tbd.C--R.sub.5

wherein R₄ and R₅ are the same or different and are each hydrogen,loweralkyl having 1-6 carbon atoms, carboxyalkyl, carboxamido,carboxamidoalkyl, carboxamidodialkyl, or phenyl.

The above acetylene compound is reacted with the chosen1-loweralkyl-5-nitroimidazol-2-hydroxamoyl chloride of the followingstructure: ##STR5## wherein R₁ is hydrogen, loweralkyl having 1-6 carbonatoms, or CH₂ CH₂ OH, to prepare the isoxazolyl derivative. Thehydroxamoyl chloride is prepared from the2-formyl-1-substituted-5-nitroimidazol following procedures known in theart. For example, reaction with hydroxylamine is followed bychlorination with nitrosyl chloride. Preparation of the 2-formylstarting material is described in Belgium Pat. No. 661,262 issued Sept.17, 1965.

The acetylene and the hydroxamoyl chloride are reacted in an inertsolvent such as tetrahydrofuran, benzene, or chloroform. The molar ratioof the hydroxamoyl chloride to the acetylene is approximately 1:1,although 1:1-15 can be used. The reaction takes place in the presence ofan organic base, such as an alkylamine, for example, triethylamine,N-methyl piperidine, or any suitable tertiary amine. The temperature ofthe reaction is preferably 0°-25° C. Lower temperatures may be used, to-20° C., and the operable upper temperature limit is such thatsubstantially no acetylene polymerization occurs. The reaction takesplace in from 1/2 to 10 hours.

It is noted that neither the reactive olefin nor the reactive acetylenecontain the substituents amino, aminoalkyl, or aminodialkyl, althoughthis moiety can be present on the final nitroimidazole. The process ofpreparing these functions utilizes first an olefin or an acetylenecontaining either a carboxyalkyl or a carboxamido group at any one ofpositions R₂, R₃, R₄, or R₅. The reaction with the desirednitroimidazole is completed as described above; the final isoxazolyl-,Δ² -isoxazolinyl-, or isoxazolidinyl-nitroimidazole is prepared. Thisnitroimidazole is then hydrolyzed in acidic or basic aqueous solution toremove either the carboxyalkyl group or the carboxamido group, therebyproducing the free carboxylic acid functionality at positions R₂, R₃,R₄, or R₅ of the corresponding ring. Following hydrolysis, the acidchloride is prepared by reacting with thionyl chloride or oxalylchloride. The acid chloride is then reacted with an alkali metal azide,such as sodium, potassium, or lithium azide to prepare the acid azide ofthe nitroimidazole. This latter acid azide can be rearranged to thecorresponding isocyanate by heating to reflux in an inert organicsolvent such as benzene, xylene, or the like. The isocyanate can betreated with mineral acid such as HCl, H₂ SO₄ or the like to prepare thefree amino substituent. Alternately, the isocyanate can be reacted atelevated temperatures with methanol in an inert organic solvent as aboveto prepare the carbamate, and the latter removed by acid or basehydrolysis to yield the final amine.

After the amine is obtained on the ring, the nitroimidazole can betreated with a loweralkyl halide, loweralkyl having 1-6 carbon atoms,for instance, methyl iodide, ethyl chloride, n-butyl iodide, hexylbromide, or the like. An inert organic solvent such as ethanol,methanol, dimethyl formamide, and an elevated temperature between60°-120° C. can be used. The amino group at R₂, R₃, R₄, or R₅ is thenalkylated within 1-2 hours. If a molecular equivalent is used, thesecondary amine is produced, or an aminoalkyl group at R₂, R₃, R₄, orR₅. If an excess of reagent is used, the tertiary amine, theaminodialkyl group, is produced at R₂, R₃, R₄, or R₅. If anunsymmetrical tertiary amine is desired, the reaction can be conductedin two stages, with a molecular equivalent of each desired alkyl halidebeing used in each step.

The above described acetylene can only be used to prepare an isoxazolylderivative in which R₄ and R₅ are not joined in a ring structure. Whenan isoxazolyl derivative is desired which has a cyclic substituent onpositions 4 and 5 of the isoxazole ring, a morpholino-substituted olefinhaving the following formula: ##STR6## wherein N is an integer from 3 to10, can be reacted with the hydroxamoyl chloride in the presence of anorganic base, such as triethylamine. An inert solvent system is used,for instance, tetrahydrofuran is suitable. The reaction takes place infrom 1/2 to 2 hours at 0°-25° C. The compound thus prepared is amorpholine-substituted Δ² -isoxazoline having the following formula:##STR7## This latter compound can be isolated, and treated with a strongmineral acid to remove the element of morpholine thereby preparing thedesired compound: ##STR8##

The Δ² -isoxazolinyl derivatives are also prepared from the1-loweralkyl-5-nitroimidazol-2-hydroxamoyl chloride by reaction of thelatter with the olefin defined above. There are two different sets ofprocess conditions. In one route, the olefin and the hydroxamoylchloride are reacted in an inert solvent at reflux. The solvent ischosen so that the reflux temperature is preferably 100°-150° C., andcan be 80°-200° C. The ratio of hydroxamoyl chloride to olefin isapproximately 1:1, although 1:1-15 can be used. The reaction takes placein about 18 to 24 hours.

The other route used to prepare the Δ² -isoxazolinyl derivative utilizesthe presence of an organic base, such as alkylamine, for example,triethylamine, N-methyl piperidine or any other suitable tertiary amine.The reaction takes place in a solvent such as tetrahydrofuran at lowtemperatures, preferably from 0°-25° C. The reaction takes place in from1/2 to 10 hours.

The isoxazolindinyl derivatives are prepared by reacting an olefin asdescribed above with an α-(1 methyl-5-nitroimidazol-2-yl)-N-alkylnitroneof the following formula: ##STR9## wherein R₁ is hydrogen, loweralkylhaving 1-6 carbon atoms, or CH₂ CH₂ OH, and Y is H, loweralkyl orbenzyl. This nitrone can be prepared from a2-formyl-1-substituted-5-nitroimidazole by reaction with a benzyl- oralkyl-substituted-hydroxylamine, such as ##STR10## wherein Y ishydrogen, a benzyl radical or an alkyl radical having 1-6 carbon atoms.The hydroxylamine can preferably be employed in the salt form, such asthe hydrochloride, acetate, carbonate and others, or in the free baseform. The two reactants are mixed together and allowed to react at roomtemperature to 60° C. for 2-12 hours in a solvent such as methanol,ethanol, or water. The desired product can be isolated after thesolution is made alkaline with an inorganic base.

The chosen nitrone is then reacted with an olefin chosen from the groupdescribed above. The reactants are reacted in an inert solvent atreflux, and operably at a temperature of about 80°-200° C., andpreferably 100°-150° C. The ratio of nitrone to olefin is approximately1:1, although 1:1-15 can be used. The reaction takes place in about 1-12hours.

The novel compounds of this invention have anti-bacterial andantiprotozoal activity especially against human and animaltrypanosomiasis, including Chagas' disease, and trichomoniasis.

Trypanosomiasis is a term used to described a group of allied protozoaldiseases, each of which is due to infection with a species of the genusTrypanosoma. They reach their greatest importance in Africa where theirpresence in enzootic form precludes the keeping of domestic animalsthroughout the largest part of the continent between 15° N and 20° Slatitude. The pathogenic trypanosomes of Africa are considered to beprimarily associated with the tsetse flies (glossina) which feed onvertebrate blood. Wherever tsetse are present, trypanosomiasis will alsobe found in some part of the mammalian population. The clinical findingsare typically those of a wasting disease with intermittent fever.Anemia, edema, and cachexia are parts of the syndrome.

The important trypanosomes pathogenic to domestic animals are T.congolense, T. simiae, T. vivax, and T. brucei. The latter trypanosomeis morphologically identical to T. gambiense, responsible for human"sleeping sickness" of Africa. A trypanosome found in the WesternHemisphere is T. cruzi, which affects both domestic animals and man.

Acute Chagas' disease (T. cruzi) occurs predominantly in young children.The chronic form may be mild and asymptomatic, but complications frommyocarditis and C.N.S. involvement may result with fatal outcome.

Trichomoniasis is a protozoan disease affecting cattle, poultry, andhumans. In cattle the causative protozoan is Trichomonas foetus whichproduces a contagious venereal disease characterized by sterility,pyometra and abortion. Trichomonas gallinarum invades the lowerintestine of domestic birds and causes diarrhea and lesions in theintestinal wall. In humans the infective protozoa are Trichomonasvaginalis, infecting the vagina and prostate, and Trichomonas hominis,found in the intestine.

The compounds of this invention have particular value in the control oftrypanosomiasis and trichomoniasis in domesticated animals, particularlycattle. For this purpose, they may be administered orally with aningestible carrier as a component of the animal feedstuff, in thedrinking water, in salt blocks and in unit dosage forms such as bolusesand drenches. The amount of active ingredient required for optimumcontrol of trypanosomiasis varies in accordance with such factors as theparticular compound employed. The species of animal to be treated, thespecies of infecting parasite, the severity of infection, and whetherthe compound is employed therapeutically or prophylactically. Ingeneral, the compounds defined by Formula I, when administered orally todomestic animals in daily doses of from about 0.1 mg. to about 500 mg.per kilogram of animal body weight are highly effective in controllingtrypanosomiasis and trichomoniasis without intolerable toxic effect.When these compounds are to be employed as therapeutic agents, goodresults are obtained when the animals are fed a daily dose of from about5 mg. to about 500 mg. and preferably 15 mg. to 250 mg. per kilogram ofbody weight.

Administration may be in a single dose or divided into a plurality ofsmaller doses over a period of 24 hours. Where prophylactic treatment isdesired and the compounds are fed continuously, satisfactory results areobtained when the animals ingest daily dosages of about 0.1 mg. to 100mg. per kilogram of body weight. The unit dosage forms may be readilyprepared by conventional formulating techniques and are particularlyuseful when administration is to be made in a single dose or divideddoses over a period of 24 hours.

The exact amount of active ingredient to be employed in the abovecompositions may vary provided that a sufficient amount is ingested togive the required dosage. In general, tablets, boluses and drenchescontaining from about 5 to 70% by weight of active ingredient may besatisfactorily employed to supply the desired dosage.

The substituted imidazoles defined by Formula I above may beadministered, dispersed in or admixed with the normal elements of animalsustenance, i.e., the feed, drinking water or other liquids normallypartaken by the animals. This method is preferred when it is desired toadminister the active compounds continuously, either as a therapeutic orprophylactic agent, for a period of several days or more. However, insuch usage, it is to be understood that the present invention alsocontemplates the employment of compositions containing the activecompounds intimately dispersed in or admixed with any other carrier ordiluent which is inert with respect to the active ingredient, orallyadministrable and is tolerated by the animals.

When the compounds described according to Formula I above are providedas a constituent of the feed, the required dosage may be supplied withfeed compositions containing from about 0.001 to 3% by weight of theactive compound. Such medicated feed compositions can be prepared fordirect use by mixing the above amount of active ingredient directly withthe feed. The medicated feeds may also be prepared by the use of feedsupplements containing a higher concentration of the active ingredientuniformly dispersed in a solid edible carrier such as corn meal, wheatshorts, alfalfa, etc. In general, feed supplements containing from about5% to about 50% by weight of active ingredient may be satisfactorilyemployed to supply the desired dosage in the finished feed.

In the preparation of feed supplements, the active ingredient is addedto the carrier and the whole mixed to give substantially uniformdispersion of the anti-trypanosomiasis agent in the carrier.

When the substituted nitroimidazoles of this invention are used in theprevention and treatment of Chagas' disease and human "sleepingsickness," the compounds can be administered as intravenous,intramusclar, or interperitoneal injections. The compounds are suspendedor dissolved in an inert non-toxic pharmaceutically acceptable carrierand administered. When used as a prophylactic, 2-12 mg./kg. of bodyweight are injected every 1-8 months. The compounds can also be usedorally against Chagas' disease or human sleeping sickness. The oraldosage is 3-20 mg. per kg. twice a day for 5-10 days. This therapy canbe per kg. twice a day for 5-10 days. This therapy can be given along orin addition to other drugs useful against trypanosomiasis, such assodium suramin, melarsoprol, tryparsamide, or pentamidine.

The compounds of the present invention are also useful as topicaltrichomonacides. When employing the compounds in this manner, one ormore of the active agents are uniformly distributed in a suitablechemotherapeutic vehicle that is chemically compatible with theparticular compound selected, non-inhibiting with respect to the actionof the effective agent upon the parasite and essentially non-injuriousto body tissue under the conditions of use. The vehicle is preferably asemi-liquid or semi-solid type and the final preparation may be in theform of a suppository if desired.

Oil and water types of emulsions or creams as well as aqueous jelliessuch as those prepared with the aid of any of a number of commerciallyused jelling agents including acacia, tragacanth, bentonite, alginicacid and the like are suitable vehicles. The vehicle may also be aviscous aqueous gel containing one or more cellulose derivatives such asmethyl cellulose, hydroxyethyl cellulose, and sodium carboxymethylcellulose. Gelling agents such as pectin, gum tragacanth, sodiumalginate and other vegetable gelling agents are also useful vehicles inthis regard.

This invention is more fully described in a reading of the followingexamples. The first four examples show the preparation of the5-nitroimidazole starting materials. These preparations are exemplaryonly to show one of several possible methods of preparing thesecompounds.

EXAMPLE 1 1-Methyl-5-nitroimidazole

24.2 G., (0.214 moles) of 4(5)-nitroimidazole is heated with 24.0 g.(0.11 mole) of methyl tosylate for 1 hour at 180°-190° C. and cooled togive a hard solid. The mixture is shaken with 175 ml. of 2.5 N aqueoussodium hydroxide until it is dissolved and diluted with 175 ml. of waterto give an oily precipitate. The mixture is extracted with ether; theether extract washed with 2.5 N aqueous hydrochloric acid and water. Theaqueous acid wash is treated with excess aqueous sodium hydroxide andextracted with ether. This latter ether extract is evaporated to drynessand recrystallized from petroleum ether to yield1-methyl-5-nitroimidazole, m.p. 154°-155° C.

In accordance with the above procedure but starting with ethyl tosylate,propyl tosylate, or n-butyl tosylato in place of methyl tosylate, thereis obtained 1-ethyl-5-nitroimidazole, 1-propyl-5-nitroimidazole, and1-n-butyl-5-nitroimidazole.

EXAMPLE 2 1-Methyl-2-hydroxymethyl-5-nitroimidazole

27.9 g. of 1-methyl-5-nitroimidazole prepared as in Example 1 and 30.1g. of paraformaldehyde are added to 154 ml. of dimethylsulfoxide and theresulting solution is sealed into a glass-lined tube. The solution isheated at 110° C. for 24 hours, with shaking. The dimethylsulfoxide isremoved by distillation at 53°-56° C./2 mm. The residue is extractedwith 3 × 150 ml. of hot benzene. The benzene extracts are combined andcooled to room temperature. 1-Methyl-2-hydroxymethyl-5-nitroimidazolecrystallizes, and is recovered by filtration. The yield of product is 23g., m.p. 112°-114.5° C.

When 1-ethyl-5-nitroimidazole, 1-propyl-5-nitroimidazole,1-n-butyl-5-nitroimidazole, and 4(5)-nitroimidazole are used in theabove reaction, respectively, the following compounds are prepared:1-ethyl-2-hydroxymethyl-5-nitroimidazole;1-propyl-2-hydroxymethyl-5-nitroimidazole;1-n-butyl-2-hydroxymethyl-5-nitroimidazole; and2-hydroxymethyl-5-nitroimidazole.

EXAMPLE 3 1-Methyl-2-formyl-5-nitroimidazole

100 g. (0.64 mole) of 1-methyl-2-hydroxymethyl-5-nitroimidazole preparedas in Example 2 is dissolved in 3500 ml. of benzene at 70° C. There isadded over a 20 minute period 460 g. of lead tetraacetate (previouslywashed with glacial acetic acid and air dried in the dark). The reactionmixture is stirred at 78° C. for 8 hours during which time white,crystalline lead diacetate precipitates from the solution. The mixtureis allowed to stand overnight at room temperature, and the leaddiacetate then removed by filtration and washed with 2 × 100 ml. ofbenzene. The combined benzene filtrate and washes are extracted with1500 ml. of water and then with two 1 liter portions of saturatedaqueous potassium bicarbonate.

The dried extracts are evaporated in vacuo to give a residue ofsubstantially pure 1-methyl-2-formyl-5-nitroimidazole. Recrystallizationof the product from 500 ml. of boiling hexane affords 79 g. of1-methyl-2-formyl-5-nitroimidazole, m.p. 90°-94° C.

When this general procedure is followed using1-ethyl-2-hydroxymethyl-5-nitroimidazole,1-propyl-2-hydroxymethyl-5-nitroimidazole,1-n-butyl-2-hydroxymethyl-5-nitroimidazole, and2-hydroxymethyl-5-nitroimidazole, the following compounds arerespectively prepared: 1-ethyl-2-formyl-5-nitroimidazole;1-propyl-2-formyl-5-nitroimidazole; 1-n-butyl-2-formyl-5-nitroimidazole;and 2-formyl-5-nitroimidazole.

EXAMPLE 4 1-(2'-Acetoxyethyl)-5-nitroimidazole

4.0 g. of 4(5)-nitroimidazole and 4.7 ml. of β-ethoxyethyl tosylate areheated together in a 170°-175° C. oil bath for 1 hour with occasionalstirring until the mixture becomes homogeneous. The mixture is cooled tonear room temperature and dissolved by agitating with a mixture of about50 ml. of chloroform and 50 ml. 4N ammonium hydroxide. The chloroformphase is extracted twice with 2N ammonium hydroxide and dried oversodium sulfate. Evaporation to dryness in vacuo gives a black syrupwhich is filtered through 30 g, of basic alumina eluting with1,2-dichloroethane ether. The very pale yellow band which comes throughthe column fairly rapidly is collected and evaporated in vacuo to give ayellow oil which crystallizes on seeding. The crude product isrecrystallized from ether-hexane giving pale brown crystals of 1(2'-ethoxyethyl)-5-nitroimidazole.

57 mg. of the above product is heated at 100° C. in .3 ml. concentratedsulfuric acid for 1/2 hour. The mixture is diluted with 1.5 ml. waterand heated an additional hour. The solution is treated with charcoal,diluted with 1 ml. water and treated dropwise with 0.7 ml. of 11.7 Nsodium hydroxide while cooled in ice. The crystalline precipitate whichforms is filtered off, washed with water and air dried. This material isrecrystallized from benzene and then with charcoal treatment frommethanol-water giving 1-(2'-hydroxyethyl)-5-nitroimidazole, m.p.101°-102° C.

Acetylation of 15 g. of the latter product with 10 g. of aceticanhydride in 30 ml. of pyridine at reflux for 20 minutes yields1-(2'-acetoxyethyl)-5-nitroimidazole, m.p. 61°-62° C.

EXAMPLE 5 1-(2'-Acetoxyethyl)-2-formyl-5-nitroimidazole

A mixture of 24.25 g. of 1-(2'-acetoxyethyl)-5-nitroimidazole preparedas in Example 4, 15 g. of paraformaldehyde and 150 ml. ofdimethylsulfoxide is heated in a sealed tube overnight at 100°-150° C.The dimethylsulfoxide is removed completely at reduced pressure, and theresidue is dissolved in water and extracted with chloroform. Thechloroform extract is dried and concentrated. The residue is dissolvedin ethyl acetate, and the solution is charged on a column of alumina.Elution with ethyl acetate and evaporation of the solvent yields1-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole, m.p. 38°-145° C.

This compound is then treated following the procedure of Example 1 withlead tetraacetate. After purification,1-(2'-acetoxyethyl)-2-formyl-5-nitroimidazole is identified.

This latter compound can be used in any of the following Examples whichuse the starting 2-formyl-1-substituted-5-nitroimidazoles of Example 3.After using this compound to form the desired cyclic-substitutednitroimidazole, the acetate can be removed using hydrolysis to yield thedesired 1-(2'-hydroxyethyl)-2-substituted-5-nitroimidazole.

The following Example, Example 6, shows the preparation of the nitroneof Formula III. Example 7 is the preparation of the hydroxyamoylchloride of Formula II.

EXAMPLE 6 α-(1-Methyl-5-nitroimidazol-2-yl)-N-methylnitrone

To a solution of 1-methyl-2-formyl-5-nitroimidazole prepared as inExample 3, (4.65 g., 0.03 mole) in 75 ml. of methanol is added 2.5 g.(0.03 mole) of N-methylhydroxylamine hydrochloride CH₃ NHOH.HCl. Themixture is allowed to stand at room temperature for 4 hours. Aprecipitate forms which is recovered and dissolved in 40 ml. of water.Solid sodium bicarbonate is added until the solution has a basic pH anda precipitate deposits again. After filtration and recrystallizationfrom methanol, 1.8 g. of the product,α-(1-methyl-5-nitroimidazol-2-yl)-N-methylnitrone is recovered having amelting point of 180° C. (with decomposition).

The corresponding α-(1-ethyl-5-nitroimidazol-2-yl)-N-methylnitrone,α-(1-propyl-5-nitroimidazol-2yl)-N-methylnitrone, andα[1-(2'-acetoxyethyl)-5-nitroimidazol-2-yl]-N-methylnitrone can beprepared in a similar fashion utilizing the respectively1-substituted-2-formyl-5-nitroimidazoles disclosed in Examples 3 and 5.The corresponding α-(1-methyl-5-nitroimidazol-2-yl)-N-benzylnitrone canalso be prepared using N-benzylhydroxylamine hydrochloride in the abovereaction with 1-methyl-2-formyl-5-nitroimidazole.

EXAMPLE 7 1-Methyl-5-nitroimidazole-2-hydroxamoylchloride

15.5 g. of 1-methyl-2-formyl-5-nitroimidazole prepared as in Example 3is dissolved in 300 ml. of ethanol and heated to 80° C. The mixture isadded to a hot solution of 7.65 g. of NH₂ OH.HCl in 30 ml. of water. Themixture is refrigerated overnight. Filtration and crystallizationyielded a yellow crystalline material, having a melting point of251°-252° C. (dec.). This intermediate oxime product is dissolved in 50ml. of dimethylformamide at 0° C. A solution of NOCl (13.1 g. in 200 ml.of dimethylformamide) is added dropwise with stirring. The mixture isstirred at 0° C. for 15 minutes and 45 minutes at room temperature. Itis quenched by pouring into 2500 ml. of cold water, and the precipitatefiltered, washed and dried. A sample is recrystallized from ethylacetate and dried under vacuum. The product obtained has a melting pointof 185°-186° C. and is identified as1-methyl-5-nitroimidazole-2-hydroxamoylchloride. The corresponding1-(2'-acetoxyethyl)-5-nitroimidazole-2-hydroxamoylchloride,1-ethyl-5-nitroimidazole-2-hydroxamoylchloride,1-n-butyl-5-nitroimidazole-2-hydroxamoylchloride, and5-nitroimidazole-2-hydroxamoylchloride are prepared respectively from1-(2'-acetoxyethyl)-2-formyl-5-nitroimidazole,1-ethyl-2-formyl-5-nitroimidazole, 1-n-butyl-2-formyl-5-nitroimidazole,and 2-formyl-5-nitroimidazole prepared as in Examples 3 and 5.

The following Examples 8 to 35 all have the structural formula given.However, only the oxygen-containing ring is drawn. When the NI is used,it is meant to be the correspoinding nitroimidazol-2-yl ring.

EXAMPLE 81-Methyl-2-(2-methyl-5-carboxymethyl-isoxazolindin-3-yl)-5-nitroimidazole##STR11##

The compound prepared in Example 6,α-(1-methyl-5-nitroimidazol-2-yl)-N-methylnitrone (4.0 g.) is added to50 ml. of methylacrylate and is refluxed at about 80° C. for 1 hour. Atthe end of this time, excess methylacrylate is removed under vacuum. Theresidue is purified by recrystallization from methanol. The productrecovered is identified as1-methyl-2-(2-methyl-5-carboxymethyl-isoxazolindin-3-yl)-5-nitroimidazolehaving a melting point of 105°-106° C. The corresponding benzylderivative,1-methyl-2-(2-benzyl-5-carboxymethyl-isoxazolindin-3-yl)-5-nitroimidazoleis prepared using α-(1-methyl-5-nitroimidazol-2-yl)-N-benzylnitrone.

EXAMPLE 91-Methyl-2-(2-methyl-4,5-hexamethylene-isoxazolindin-3-yl)-5-nitroimidazolehydrochloride ##STR12##

1.87 g. of the compound prepared in Example 6,α-(1-methyl-5-nitroimidazol-2-yl)-N-methylnitrone, and 1.1 g. ofcyclooctene are added in 30 ml. of toluene. The mixture is refluxed forabout 16 hours. At the end of this period, the nitrone is dissolved. Thereaction mixture, after filtering, is evaporated to a yellow oil. Thisoil is purified by chromatographic techniques on silica gel with abenzene:chloroform eluent. 2.5 g. of a clear yellow oil is obtained.This oil is then mixed with ether containing dry hydrochloric acid toobtain 2.4 g. of a crystalline material. After recrystallization from2-propanol, a solid is obtained having a melting point of 193° C. withdecomposition. This solid is identified as1-methyl-2-(2-methyl-4,5-hexamethylene-isoxazolindin-3-yl)-5-nitroimidazolehydrochloride. The analogous compound prepared usingα-(1-methyl-5-nitroimidazol-2-yl)-N-benzylnitrone is identified as1-methyl-2-(2-benzyl-4,5-hexamethylene-isoxazolindin-3-yl)-5-nitroimidazolehydrochloride.

EXAMPLE 101-Methyl-2-(2-methyl-5-carboxamido-isoxazolindin-3yl)-5-nitroimidazole##STR13##

5.52 g. of the nitrone prepared in Example 6 is refluxed with 2.34 g. ofacrylamide in 100 ml. of tetrahydrofuran. After 3 hours, an additional1.0 g. of acrylamide in 40 ml. of tetrahydrofuran is added and refluxingcontinued. After 12 hours, the reaction mixture is cooled and filtered.After purification, 3.4 g. of the product,1-methyl-(2-methyl-5-carboxamido-isoxazolindin-3-yl)-5-nitroimidazole,having a melting point of 214°-215° C. (dec.) is recovered. Thecorresponding1-methyl-2-(2-benzyl-5-carboxamido-isoxazolindin-3-yl)-5-nitroimidazoleis prepared using the N-benzylnitrone described in Example 6.

The product1-methyl-2-(2-methyl-5-carobxamido-isoxazolindin-3-yl)-5-nitroimidazoleis then heated in an acidic solution to recover the hydrolysis product,1-methyl-2-(2-methyl-5-carboxylicacid-isoxazolindin-3-yl)-5-nitroimidazole. This latter product, aftertreating following the procedure of Example 13, yields1-methyl-2-(2-methyl-5-amino-isoxazolindin-3-yl)-5-nitroimidazole.

EXAMPLE 111-Methyl-2-[2-methyl-5-(N-methyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazole##STR14##

5.4 g. of the nitrone prepared in Example 6 is refluxed with 2.5 g. ofN-methylacrylamide in 100 ml. of tetrahydrofuran. After 2 hours, anadditional 1.0 g. of N-methylacrylamide in 40 ml. of tetrahydrofuran isadded and refluxing continued. After 8 hours, the reaction mixture iscooled and filtered. After purification, the product,1-methyl-2-[2-methyl-5-(N-methyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazole,is recovered.

In an analogous manner, using N-benzylnitrone and N-ethylacrylamide; orN-benzylnitrone and N-hexylacrylamide, the corresponding products,1-methyl-2-[2-benzyl-5-(N-ethyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazoleand1-methyl-2-[2-benzyl-5-(N-hexyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazoleare prepared.

Also, when N,N-dimethylacrylamide or N-methyl-N-propylacrylamide areemployed in the above reaction with the nitrone as prepared in Example6, the products1-methyl-2-[2-methyl-5-(N,N-dimethyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazoleand1-methyl-2-[2-methyl-5-(N-methyl-N-propyl)-carboxamido-isoxazolindin-3-yl]-5-nitroimidazoleare formed.

EXAMPLE 12 1-Methyl-2-(5-carboxyethylisoxazol-3-yl)-5-nitroimidazole##STR15##

8.2 g. of the hydroxamoylchloride prepared in Example 7 are dissolved in160 ml. of tetrahydrofuran at 0° C. To the solution is added a coldsolution of triethylamine tetrahydrofuran (0.04 mole in 40 ml.). Afterone minute, a solution of ethylpropiolate (5.0 g.) in 10 ml. oftetrahydrofuran is added. The reaction mixture is stirred at 0° C. for1/2 hour and then at room temperature for 1 hour. The mixture is thenfiltered and the filtrate is reduced under vacuum leaving an orangecrystalline mass. After recrystallization from ethanol, the product isobtained which has a melting point of 114°-115 C. This product isidentified as 1-methyl-2-(5-carboxyethylisoxazol-3-yl)-5-nitroimidazole.

EXAMPLE 13 1-Methyl-2-(5-carboxamido-isoxazol-3-yl)-5-nitroimidazole##STR16##

3 g. of the compound prepared in Example 12 is dissolved in hotmethanol. The solution is saturated with ammonia. A precipitate isformed and the mixture is cooled by placing in the refrigerator. Afterfiltration and purification, the pure product having a melting point of235°-238° C. is recovered. This product is identified as1-methyl-2-(5-carboxamide-isoxazol-3-yl)-5-nitroimidazole.

EXAMPLE 14 1-Methyl-2-(5-aminoisoxazol-3-yl)-5-nitroimidazole1-Methyl-2-(5-aminomethylisoxazol-3-yl)-5-nitroimidazole1-Methyl-2-(5-aminomethylhexylisoxazol-3-yl)-5-nitroimidazole

4 g. of the compound prepared in Example 13,1-methyl-2-(5-carboxamidoisoxazol-2-yl)5-nitroimidazole, are dissolvedin 30 ml. of a 10% HCl solution, and the mixture heated to reflux. After30 minutes, the reaction is terminated and the product,1-methyl-2-(5-carboxylic acid-isoxazol-3-yl)-5-nitroimidazole, isobtained.

1.5 g. of the acid prepared above are refluxed in oxalyl chloride (25ml.) until a clear solution is obtained, after about 6 hours. Excessreagent is removed under vacuum. The product, 1-methyl-2-(5-carboxylicacid chloride-isoxazol-3-yl)-5-nitroimidazole is dissolved in 50 ml.acetone. A solution of sodium azide (0.4 g. of NaN₃) in 5 ml. of wateris added all at once. After stirring for 15 minutes, an additional 100ml. of water is added and stirring continued for another 15 minutes. Theproduct is 1-methyl-2-(5-carboxylic acidazideisoxazol-3-yl)-5-nitroimidazole. 1.4 g. of the latter is dissolvedin 60 ml. of benzene and refluxed for 3 hours. 10 ml. of concentratedHCl are then added and refluxing continued for 1/2 hour. The reaction isdiluted with chloroform and made basic. The dried organic phase yielded0.5 g. of the product,1-methyl-2-(5-aminoisoxazol-3-yl)-5-nitroimidazole, m.p. 180°-185° c.

0.25 g. of 1-methyl-2-(5-aminoisoxazol-3-yl)-5-nitroimidazole, preparedabove, are dissolved in 20 ml. of dimethylformamide. 0.16 g. of methyliodide are added, and the reaction mixture is heated to 80° for 1 hour.The solvent and unreacted reagents are removed, and the productrecrystallized. The product is1-methyl-2-(5-aminomethyl-isoxazol-3-yl)-5-nitroimidazole.

The product prepared above is treated in a similar fashion with hexylchloride in dimethylformamide for 2 hours. The recrystallized product isidentified as1-methyl-2-(5-aminoethylhexylisoxazol-3-yl)-5-nitroimidazole.

EXAMPLE 151-Methyl-2-(4,5,6,7-tetrahydrocyclohex[d]isoxazol-3-yl)-5-nitroimidazole##STR17##

To a suspension of 2.04 g. of the hydroxamoyl chloride prepared inExample 7 in 30 ml. of tetrahydrofuran at 0° C. is added a solution oftriethylamine and 1-morpholino-3,4,5,6-tetrahydrobenzene (1.01 g. oftriethylamine and 1.67 g. of the morpholino compound). The mixture isstirred 15 minutes at 0° C. and 1/2 hour at room temperature. Thetetrahydrofuran is evaporated. The residue is dissolved indichloromethane and is washed with sodium bicarbonate solution. Theorganic phase is dried and evaporated to a yellow oil. After treatmentwith diethyl ether, a crystalline product is obtained. A samplerecrystallized from methanol has a melting point of 153°-156° C. Thisproduct is an intermediate in the synthesis and is a Δ² -isoxazolinecompound with a morpholino substituent. It is identified as1-methyl-2-(4,5-tetramethylene-5-morpholino-Δ²-isoxazolindin-3-yl)-5-nitroimidazole, m.p. 155° C.

This latter morpholino compound (10 g.) is dissolved in concentratedsulfuric acid (100 ml.) and heated on a steam bath for 11/2 hours. Theyellow reaction mixture is poured into ice to quench. After filtration,a crude product is obtained. It is recrystallized from methanol andyields 4.5 g. of a product identified as1-methyl-2-(4,5,6,7-tetrahydrocyclohex[d]isoxazol-3-yl)-5-nitroimidazole,having a melting point of 161°-162° C.

The following Examples 16 through 36 relate to the preparation of the Δ²-isoxazoline. It will be clear to one skilled in the art that, althoughthe 1-methyl derivatives are prepared, the other loweralkyl,acetoxyethyl, and unsubstituted derivaties can be prepared from thecorresponding hydroxamoyl chloride compounds in Example 7.

EXAMPLE 16 1-Methyl-2-(5-carboxymethyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR18##

To a solution of the hydroxamoyl chloride compounds prepared in Example7 in tetrahydrofuran (4.02 g. in 80 ml.) at 0° C. is added with stirring2.7 ml. of methylacrylate. Following this addition, a solution oftriethylamine in tetrahydrofuran (2.02 g. in 20 ml.) is added dropwiseto the solution. The mixture is stirred 10 minutes at 0° C. then onehour at room temperature. The triethylamine hydrochloride is filteredand then tetrahydrofuran is removed under vacuum. The residue is takenup in chloroform and washed with a dilute solution of sodiumbicarbonate. After drying, the organic layer is evaporated and theresidual yellow oil is crystallized. The product is identified as1-methyl-2-(5-carboxymethyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole, andhas a melting point of 109°-110° C.

EXAMPLE 17 1-Methyl-2-(5-carboxamido-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR19##

The compound prepared in Example 16 is dissolved in methanol (119 mg. in10 ml.). Ammonia is bubbled through the solution until a precipitateformed. The mixture is filtered after one hour and purification andrecrystallization yield 95 mg. of the product,1-methyl-2-(5-carboxamido-Δ² -isoxazolin-3-yl)-5-nitroimidazole, havinga melting point of 238°-239° C. This latter compound can be treatedfollowing the procedure of Example 14 to yield 2-(5-amino-Δ²-isoxazolin-3-yl)-5-nitroimidazole.

EXAMPLE 18 1-Methyl-2-(5-phenyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole##STR20##

2.04 g. of the hydroxyamoylchloride prepared in Example 7 are dissolvedin 40 ml. of tetrahydrofuran. One gram of styrene is added and thesolution is kept at 0° C. while a solution of triethylaminetetrahydrofuran (1.01 g. in 10 ml.) is added. The mixture is stirred 15minutes at 0° C. and 1 hour at room temperature. After filtering andremoving the excess solvent, the residue is taken up in chloroform andwashed with a dilute solution of sodium bicarbonate. Evaporation of thedried extract yields a yellow oil which recrystallizes from methanol asa pale yellow crystalline material. This material has a melting point of133°-134° C. and is identified as 1-methyl-2-(5-phenyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole.

EXAMPLE 19 1-Methyl-2-(4,5-cyclodimethylsulfone-66²-isoxazolin-3-yl)-5-nitroimidazole ##STR21##

0.408 g. of the hydroxamoylchloride prepared in Example 10 are dissolvedin 8 ml. of tetrahydrofuran at 0° C. To this solution is added dropwisewith stirring a 0.202 g. solution of triethylamine in 2 ml. oftetrahydrofuran. The mixture is stirred for 15 minutes at 0° C. and onehour at room temperature. After filtering and removing the solvent, theresidue is treated with chloroform and washed with sodium bicarbonatesolution. The dried organic layer after purification andrecrystallization yields a product identified as1-methyl-2-(4,5-cyclodimethylsulfone-Δ²-isoxazolin-3-yl)-5-nitroimidazole, having a melting point of 208°-209°C.

EXAMPLE 201-Methyl-2-(3a,5,6,7a-tetrahydro-4H-pyrano[3,2-d]-isoxazol-3-yl)-5-nitroimidazole##STR22##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withdihydropyran at 0° C. The product, after recrystallization, isidentified as1-methyl-2-(3a,5,6,7a-tetrahydro-4H-pyrano[3,2-d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 140°-142° C.

EXAMPLE 21 1-Methyl-2-(3a,4,6,6a-tetrahydro-4,6-dioxo-4H-pyrrolo[3,4-d]-Δ² -isoxazol-3-yl)-5-nitroimidazole ##STR23##

Following the same general procedure of Examples 16 through 19, thehydroxamoychloride prepared as in Example 7 is reacted with maleimide.The product, after recrystallization, is identified as1-methyl-2-(3a,4,6,6a-tetrahydro-4,6-dioxo-4H-pyrrolo[3,4-d]-Δ²-isoxazol-3-yl)-5-nitroimidazole, having a melting point of 259° C.(dec.).

EXAMPLE 22 1Methyl-2-(5-methyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole##STR24##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted with octene-1.The product, after recrystallization, is identified as1-methyl-2-(5-hexyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole, having amelting point of 50°-51° C.

EXAMPLE 23 1-Methyl-2-(Δ² -isoxazolin-3-yl)-5-nitroimidazole ##STR25##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted with ethylene.The product, after recrystallization, is identified as 1-methyl-2-(Δ²-isoxazolin-3-yl)-5-nitroimidazole, having a melting point of 103°-105°C.

EXAMPLE 24 1-Methyl-2-(4,5-cis-dimethyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR26##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withcis-2-butene. The product, after recrystallization, is identified as1-methyl-(4,5-cis-dimethyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole, havinga melting point of 83°-84° C.

EXAMPLE 25 1-Methyl-2-(4,5-trans-diemthyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR27##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withtrans-2-butene. The product after recrystallization, is identified as1-methyl-2-(4,5-trans-dimethyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole,having a melting point of 65°-67° C.

EXAMPLE 26Exo-2-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazol-3-yl)-1-methyl-5-nitroimidazole##STR28##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted with norbornene.The product, after recrystallization, is identified asexo-2-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benz-isoxazol-3-yl)-1-methyl-5-nitroimidazole,having a melting point of 124°-125° C.

EXAMPLE 27 1-Methyl-2-(5benzoyl-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]-isoxazol-3-yl)-5-nitroimidazole ##STR29##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withN-benzoyl-2,5-dihydro-pyrolle. The product, after recrystallization, isidentified as1-methyl-2-(5-benzoyl-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 153°-155° C.

EXAMPLE 28 trans-1-Methyl-2-(3a,4,5,6,7,8,9,9a-octahydrocyclooct[d]-isoxazol-3-yl)-5-nitroimidazole ##STR30##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withtrans-cyclooctene. The product, after recrystallization, is identifiedastrans-1-methyl-2-(3a,4,5,6,7,8,9,9a-octahydrocyclooct[d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 106°-109° C.

EXAMPLE 291-Methyl-2-(3a,4,5,6,7,7a-hexahydro-4H-cyclohex[d]-isoxazol-3-yl)-5-nitroimidazole##STR31##

Following the same general procedure of Examples 16 through 19, thehydroxamoylchloride prepared as in Example 7 is reacted withcyclohexene. The product, after recrystallization, is identified as1-methyl-2-(3a,4,5,6,7,7a-hexahydro-4H-cyclohex[d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 89.5°-91.5° C.

EXAMPLE 301-Methyl-2-(3a,4,5,6,7,8,9,9a-octahydrocyclooct[d]-isoxazol-3-yl)-5-nitroimidazole##STR32##

408 mg. of the hydroxamoylchloride prepared in Example 7 and 224 mg. ofcyclooctene are added to 6 ml. of toluene and refluxed for 14 hours. Themixture is cooled and passed through a thin-layer chromatographic colmnof 10 g. of silica gel, using benzene as an eluent. The fractionscontaining the product are reduced to yield a yellow crystallinematerial. This product is recrystallized from hexane, yielding theproduct,1-methyl-2-(3a,4,5,6,7,8,9,9a-octahydrocyclooct[d]-isoxazol-3-yl)-5-nitroimidazle,having a melting point of 113.5° to 115° C.

EXAMPLE 311-Methyl-2-(3a,4,5,6,7,7a-hexahydro-1,2-benz-isoxazol-3-yl)-5-nitroimidazole##STR33##

Following the same procedure as in Example 30, the hydroxamoylchlorideprepared as in Example 7 is reacted with cyclohexene. The product,2-(3a,4,5,6,7,7a-hexahydro-1,2-benz-isoxazol-3-yl)-5-nitroimidazole hasa melting point of 119°-121° C.

EXAMPLE 321-Methyl-cis-2-(3a,5,6,7,8,8a-hexahydro-4H-cyclohept[d]-isoxazol-3-yl)-5-nitroimidazole##STR34##

Following the same procedure as in Example 30, the hydroxamoylchlorideprepared as in Example 7 is reacted with cycloheptene. The product,1-methyl-cis-2-(3a,5,6,7,8,8a-hexahydro-4H-cyclohept[d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 93°-95° C.

EXAMPLE 331-Methyl-trans-2-(3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododec[d]-isoxazol-3-yl)-5-nitroimidazole##STR35##

Following the same procedure as in Example 30. the hydroxamoylchlorideprepared as in Example 7 is reacted with cyclododecene. The product,1-methyl-trans-2-(3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododec[[d]-isoxazol-3-yl)-5-nitroimidazole,having a melting point of 121°-122° C.

EXAMPLE 34 1-Methyl-2-(trans-4,5-dipropyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR36##

6.12 g. of the hydroxamoylchloride prepared as in Example 7 is refluxedwith 3.4 of trans-4-octene for 18 hours. The reaction mixture is thenworked up following a similar procedure as in Example 30, The productobtained, 1-methyl-2-(trans-4,5-dipropyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole, has a melting point of 34°-36° C.

EXAMPLE 35 1-Methyl-2-(trans-4,5-diethyl-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR37##

Following the same procedure as in Example 34, the hydroxamoylchlorideis reacted with trans-3-hexene. The product,1-methyl-2-(trans-4,5-diethyl-Δ² -isoxazolin-3-yl)-5-nitroimidazole, hasa melting point of 66°-67° C.

EXAMPLE 36 1-Methyl-2-(4,5-hexano-ε-lactam-Δ²-isoxazolin-3-yl)-5-nitroimidazole ##STR38##

Following the same procedure as in Example 33, the hydroxamoylchlorideis reacted with 6-amino-2-hexenoic acid lactam: ##STR39## The product,1-methyl-2-(4,5-hexano-ε-lactam-Δ² -isoxazolin-3-yl)-5-nitroimidazole isrecovered.

We claim:
 1. A 1,2-disubstituted 5-nitroimidazole having the followingstructure: ##STR40##wherein R₁ is hydrogen, loweralkyl having 1 to 6carbon atoms, or CH₂ --CH₂ -OH and R is ##STR41##wherein R₄ and R₅ arethe same or different and are each hydrogen, loweralkyl having 1-6carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl,carboxamidodialkyl, amino, phenyl, aminoalkyl, or aminodialkyl whereinthe alkyl group is carboxyalkyl, carboxamidoalkyl, carboxamidodialkyl,aminoalkyl and aminodialkyl contains 1 to 6 carbon atoms; or R₄ and R₅are a ring structure of:(CH₂)_(n), n being an integar from 3-10;providedthat when only one of R₄ and R₅ are hydrogen, the substituent other thanhydrogen is in the 5-position of the ring.
 2. The compound of claim 1which is 1-methyl-2-(5-carboxamido-isoxazol-3-yl)-5-nitroimidazole.